General anesthesia is a reversible, drug-induced behavioral state comprised of unconsciousness, amnesia, analgesia and immobility with stability and control of vital physiological systems. This fundamental tool of modern medicine is crucial for allowing thousands of patients daily to safely undergo most surgical and many non-surgical procedures. Today this state is induced and maintained by administering multiple drugs that act at multiple sites in the brain and central nervous system. Emergence from general anesthesia is a passive process whereby anesthetic drugs are merely discontinued at the end of surgery and no drugs are administered to actively reverse their effects. Allowing multiple drugs to act at multiple sites without specific mechanisms to terminate their effects most likely explains a significant component of anesthesia-related morbidity; drug side effects (nausea, hypotension, respiratory depression, hypothermia) are due to actions at sites other than their intended targets whereas persistent effects (delirium, cognitive dysfunction) are due to actions at intended targets for periods longer than desired. Hence, general anesthesia, as presently produced, is highly non-specific and inefficient. Despite the central role of anesthesiology in modern healthcare, research in this field is overly focused on deciphering the anesthetic and toxic mechanisms of current drugs with little to no attention being paid to developing new approaches. The paradigm-shifting question whose answer will revolutionize anesthesiology is not, how do current anesthetics work?, but rather, how should the state of general anesthesia be designed? We hypothesize that the answer is by developing strategies to control directly the brain's natural inhibitory pathways and arousal centers. We propose to redesign general anesthesia by combining optogenetic, electrical and pharmacological manipulations in rodent models to create this behavioral state through precisely timed control of the brain's natural inhibitory pathways and its arousal centers. If successful this research will provide a new fundamental understanding of brain arousal control, and eventually, new anesthesiology practices including: neurophysiologically-designed approaches to creating general anesthesia; reduction in morbidity; improved brain function monitoring; safer anesthesia care by non-anesthesiologists; and possibly novel therapies for arousal disorders such as depression, insomnia, pain and coma. PUBLIC HEALTH RELEVANCE: In the United States, more than 100,000 patients receive general anesthesia daily to safely undergo most surgical and many non-surgical procedures Use of anesthetic drugs by non-anesthesiologists in intensive care units and outpatient settings continues to grow. At the same time, anesthesia-related morbidity, including intra-operative awareness, altered neurological development and delirium in children and cognitive dysfunction in the elderly remains a significant problem. Despite the central role of anesthesiology in modern healthcare, research in this field is stagnant; overly focused on deciphering the anesthetic and toxic mechanisms of current drugs with no attention to developing new approaches. We propose to redesign general anesthesia by combining optogenetic, electrical and pharmacological manipulations in rodent models to create this behavioral state through precisely timed control of the brain's natural inhibitory pathways and its arousal centers. If successful this research will provide a new fundamental understanding of brain arousal control, and eventually, new anesthesiology practices including: neurophysiologically-designed approaches to creating general anesthesia; reduction in morbidity; improved brain function monitoring; safer anesthesia care by non- anesthesiologists; and possibly novel therapies for arousal disorders such as depression, insomnia, pain and coma.